Tigecycline is the first antibiotic belonging to the glycylcycline class, and the first new tetracycline analogue launched in over 30 years. It acts by binding to the bacterial 30S ribosome and thereby blocking the entry of amino-acyl t-RNA molecules into the A site of ribosome. This ultimately prevents protein synthesis by halting the incorporation of amino acids into peptide chains and thus limits bacterial growth. Chemically, it is known as (4S,4aS,5aR,12aS)-9-[2-(tert-butylamino)acetamido]-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacene carboxamide and structurally represented as follows:

The U.S. Pat. No. 5,494,903 discloses tigecycline and the pharmaceutically acceptable organic and inorganic salts or metal complexes. U.S. Pat. No. RE 40,086 describes the use of tigecycline in treating and controlling bacterial infections in warm blooded animals. Owing to its poor oral bioavailability, it is advantageous to administer tigecycline parenterally. In India, it is commercialized by Wyeth Limited in strengths of 50 mg/vial as an orange lyophilized powder or cake for intravenous administration under the proprietary name TYGACIL® (tigecycline). It is indicated for treatment of the following infections in adults: (a) complicated skin and skin structure infections, including those with methicillin-resistant staphylococcus aureus (MRSA) and (b) complicated intra-abdominal infections. The standard dosage regimen for tigecycline is an initial dose of 100 mg, followed by 50 mg every 12 hours.
Several documents disclose formulations containing tigecycline and process of formulating thereof. For example, WO 2006/138641 refers to a process for manufacturing a reconstitutable lyophilized composition of tigecycline, wherein the process comprises of admixing tigecycline with water for injection (while reducing the oxygen level and maintaining the reduced oxygen level in the water for injection); lyophilizing the composition containing tigecycline and water for injection and sealing the vials containing lyophilized composition under nitrogen. Another PCT application, WO 2007/075794 describes an oral composition containing tigecycline with at least one enteric coating. It further discloses that calcium binds to tigecycline, resulting in the reduction of its water solubility which in turn may lead to a 30% to 40% loss of tigecycline due to precipitation of the calcium complex at pH 7.4. Thus, calcium binding and subsequent precipitation of the calcium/tigecycline salt may be at least partially responsible for low oral bioavailability. Hence, the disclosed oral compositions may further contain a chelating agent, like EDTA which would help in solving the problem of poor oral bioavailability of tigecycline by chelating any calcium present.
Per the TYGACIL® (tigecycline) Prescribing Information (Wyeth, India), tigecycline lyophilized powder should be reconstituted with 5.3 mL of 0.9% sodium chloride injection, USP, or 5% dextrose injection, USP, to achieve a concentration of 10 mg/mL of tigecycline. The Prescribing Information notes that the reconstituted solution should be discarded if it is not yellow to orange in color. At the concentration of 10 mg/mL, tigecycline degrades in solution and therefore, it becomes essential that these reconstituted solutions are immediately diluted to about 1 mg/mL with saline or other pharmaceutically acceptable carriers into intravenous bags for administration to patients. However, once reconstituted it may be stored at room temperature for up to 6 hours, or refrigerated at 2° C. to 8° C. for up to 24 hours. Hence, the individuals concerned with the reconstitution and administration of tigecycline injection, like doctors, attendants, other hospital staff, need administer the reconstituted formulation of tigecycline immediately to the person in need of the medicament. This makes the whole process of administering tigecycline to a person in need of it, prone to mistakes and extremely inconvenient and patient unfriendly.
The above-discussed oxidative degradations of tigecycline are decreased to a great extent by reducing the pH of tigecycline formulations. This, however lowering the pH affects the stability as it results in epimerization, which is an inherent property of tetracyclines and which is severe in case of tigecycline. Thus degradation by oxidation and/or epimerization is a major drawback while administering tigecycline to a person in need of. The PCT application WO 2006/099258 addresses this problem, and describes a formulation of tigecycline comprising a carbohydrate and an acid or buffer, which does not require immediate use and also helps in providing stability from both oxidation and epimerization for a maximum of 24 hours of admixture/dilution with a suitable carrier. However, in the present case, it has been observed that formulating together tigecycline, an edetate, and a pH-modifying agent or an antioxidant gives a stable parenteral formulation which would provide stability from degradation by oxidation as well as epimerization at least for 45 hours.